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International Journal of Molecular... Apr 2024Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial... (Review)
Review
Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.
Topics: Humans; Thrombosis; Blood Platelets; Hemostasis; Platelet Activation; Animals; Platelet Adhesiveness; Platelet Aggregation
PubMed: 38732019
DOI: 10.3390/ijms25094800 -
Journal of Biomedical Science Sep 2023Platelets are small anucleated blood cells primarily known for their vital hemostatic role. Allogeneic platelet concentrates (PCs) collected from healthy donors are an... (Review)
Review
Platelets are small anucleated blood cells primarily known for their vital hemostatic role. Allogeneic platelet concentrates (PCs) collected from healthy donors are an essential cellular product transfused by hospitals to control or prevent bleeding in patients affected by thrombocytopenia or platelet dysfunctions. Platelets fulfill additional essential functions in innate and adaptive immunity and inflammation, as well as in wound-healing and tissue-repair mechanisms. Platelets contain mitochondria, lysosomes, dense granules, and alpha-granules, which collectively are a remarkable reservoir of multiple trophic factors, enzymes, and signaling molecules. In addition, platelets are prone to release in the blood circulation a unique set of extracellular vesicles (p-EVs), which carry a rich biomolecular cargo influential in cell-cell communications. The exceptional functional roles played by platelets and p-EVs explain the recent interest in exploring the use of allogeneic PCs as source material to develop new biotherapies that could address needs in cell therapy, regenerative medicine, and targeted drug delivery. Pooled human platelet lysates (HPLs) can be produced from allogeneic PCs that have reached their expiration date and are no longer suitable for transfusion but remain valuable source materials for other applications. These HPLs can substitute for fetal bovine serum as a clinical grade xeno-free supplement of growth media used in the in vitro expansion of human cells for transplantation purposes. The use of expired allogeneic platelet concentrates has opened the way for small-pool or large-pool allogeneic HPLs and HPL-derived p-EVs as biotherapy for ocular surface disorders, wound care and, potentially, neurodegenerative diseases, osteoarthritis, and others. Additionally, allogeneic platelets are now seen as a readily available source of cells and EVs that can be exploited for targeted drug delivery vehicles. This article aims to offer an in-depth update on emerging translational applications of allogeneic platelet biotherapies while also highlighting their advantages and limitations as a clinical modality in regenerative medicine and cell therapies.
Topics: Humans; Regenerative Medicine; Blood Platelets; Cell- and Tissue-Based Therapy; Extracellular Vesicles; Hematopoietic Stem Cell Transplantation
PubMed: 37704991
DOI: 10.1186/s12929-023-00972-w -
Platelets Dec 2023The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of... (Review)
Review
The field of proteomics and its application to platelet biology, is rapidly and promisingly developing. Platelets (and megakaryocytes) are postulated as biosensors of health and disease, and their proteome poses as a tool to identify the specific health-disease hallmarks. Furthermore, the clinical management of certain pathologies where platelets are active players demands the development of alternative treatments, such is the case in patients where the balance thrombosis-bleeding is compromised, and a proteomics approach might aid at the identification of novel targets. Hereby, the mouse and human platelet proteomes and secretomes from public databases are compared, which shows that human and mouse platelets share a highly conserved proteome, considering identified proteins, and most importantly, their relative abundance. These supports, also interspecies wise, the use of the proteomics tool in the field, substantiated by a growing number of clinically relevant studies in humans or preclinical models. While the study of platelets through proteomics seems accessible and direct (. noninvasive blood sampling, enucleated), there are some points of concern regarding the quality control of samples for such proteomics studies. Importantly, the quality of the generated data is improving over the years, which will allow cross-study comparisons. In parallel, the application of proteomics to the megakaryocyte compartment has a promising but long journey ahead. We foresee and encourage the application of platelet proteomics for diagnostic/prognostic purposes even beyond hematopoiesis and transfusion medicine, and as a tool that will procure the improvement of current therapies and the development of alternative treatment options.
Topics: Humans; Animals; Mice; Blood Platelets; Proteomics; Proteome; Megakaryocytes
PubMed: 37283127
DOI: 10.1080/09537104.2023.2220415 -
Blood Advances Oct 2023Blood platelets undergo several successive motor-driven reorganizations of the cytoskeleton when they are recruited to an injured part of a vessel. These reorganizations...
Blood platelets undergo several successive motor-driven reorganizations of the cytoskeleton when they are recruited to an injured part of a vessel. These reorganizations take place during the platelet activation phase, the spreading process on the injured vessel or between fibrin fibers of the forming clot, and during clot retraction. All these steps require a lot of energy, especially the retraction of the clot when platelets develop strong forces similar to those of muscle cells. Platelets can produce energy through glycolysis and mitochondrial respiration. However, although resting platelets have only 5 to 8 individual mitochondria, they produce adenosine triphosphate predominantly via oxidative phosphorylation. Activated, spread platelets show an increase in size compared with resting platelets, and the question arises as to where the few mitochondria are located in these larger platelets. Using expansion microscopy, we show that the number of mitochondria per platelet is increased in spread platelets. Live imaging and focused ion beam-scanning electron microscopy suggest that a mitochondrial fission event takes place during platelet activation. Fission is Drp1 dependent because Drp1-deficient platelets have fused mitochondria. In nucleated cells, mitochondrial fission is associated with a shift to a glycolytic phenotype, and using clot retraction assays, we show that platelets have a more glycolytic energy production during clot retraction and that Drp1-deficient platelets show a defect in clot retraction.
Topics: Platelet Activation; Blood Platelets; Clot Retraction; Oxidative Phosphorylation; Mitochondria
PubMed: 37624769
DOI: 10.1182/bloodadvances.2023010423 -
Frontiers in Immunology 2023In November 2021, the SARS-CoV-2 Omicron variant of concern has emerged and is currently dominating the COVID-19 pandemic over the world. Omicron displays a number of...
INTRODUCTION
In November 2021, the SARS-CoV-2 Omicron variant of concern has emerged and is currently dominating the COVID-19 pandemic over the world. Omicron displays a number of mutations, particularly in the spike protein, leading to specific characteristics including a higher potential for transmission. Although Omicron has caused a significant number of deaths worldwide, it generally induces less severe clinical signs compared to earlier variants. As its impact on blood platelets remains unknown, we investigated platelet behavior in severe patients infected with Omicron in comparison to Delta.
METHODS
Clinical and biological characteristics of severe COVID-19 patients infected with the Omicron (n=9) or Delta (n=11) variants were analyzed. Using complementary methods such as flow cytometry, confocal imaging and electron microscopy, we examined platelet activation, responsiveness and phenotype, presence of virus in platelets and induction of selective autophagy. We also explored the direct effect of spike proteins from the Omicron or Delta variants on healthy platelet signaling.
RESULTS
Severe Omicron variant infection resulted in platelet activation and partial desensitization, presence of the virus in platelets and selective autophagy response. The intraplatelet processing of Omicron viral cargo was different from Delta as evidenced by the distribution of spike protein-positive structures near the plasma membrane and the colocalization of spike and Rab7. Moreover, spike proteins from the Omicron or Delta variants alone activated signaling pathways in healthy platelets including phosphorylation of AKT, p38MAPK, LIMK and SPL76 with different kinetics.
DISCUSSION
Although SARS-CoV-2 Omicron has different biological characteristics compared to prior variants, it leads to platelet activation and desensitization as previously observed with the Delta variant. Omicron is also found in platelets from severe patients where it induces selective autophagy, but the mechanisms of intraplatelet processing of Omicron cargo, as part of the innate response, differs from Delta, suggesting that mutations on spike protein modify virus to platelet interactions.
Topics: Humans; Blood Platelets; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Pandemics; COVID-19
PubMed: 37828997
DOI: 10.3389/fimmu.2023.1231576 -
Platelets Dec 2023Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these...
Ischemic cardiovascular and venous thromboembolic events are a frequent cause of death in severe COVID-19 patients. Platelet activation plays a key role in these complications, however platelet lipidomics have not been studied yet. The aim of our pilot investigation was to perform a preliminary study of platelet lipidomics in COVID-19 patients compared to healthy subjects. Lipid extraction and identification of ultrapurified platelets from eight hospitalized COVID-19 patients and eight age- and sex-matched healthy controls showed a lipidomic pattern almost completely separating COVID-19 patients from healthy controls. In particular, a significant decrease of ether phospholipids and increased levels of ganglioside GM3 were observed in platelets from COVID-19 patients. In conclusion, our study shows for the first time that platelets from COVID-19 patients display a different lipidomics signature distinguishing them from healthy controls, and suggests that altered platelet lipid metabolism may play a role in viral spreading and in the thrombotic complications of COVID-19.
Topics: Humans; COVID-19; Lipidomics; Blood Platelets; Platelet Activation; Thrombosis
PubMed: 37114418
DOI: 10.1080/09537104.2023.2200847 -
Canadian Journal of Anaesthesia =... Oct 2023Cold-stored platelets (CSP) are an increasingly active topic of international research. They are maintained at 1-6 °C, in contrast to standard room-temperature... (Review)
Review
PURPOSE
Cold-stored platelets (CSP) are an increasingly active topic of international research. They are maintained at 1-6 °C, in contrast to standard room-temperature platelets (RTP) kept at 20-24 °C. Recent evidence suggests that CSP have superior hemostatic properties compared with RTP. This narrative review explores the application of CSP in adult cardiac surgery, summarizes the preclinical and clinical evidence for their use, and highlights recent research.
SOURCE
A targeted search of MEDLINE and other databases up to 24 February 2022 was conducted. Search terms combined concepts such as cardiac surgery, blood, platelet, and cold-stored. Searches of trial registries ClinicalTrials.gov and WHO International Clinical Trials Registry Platform were included. Articles were included if they described adult surgical patients as their population of interest and an association between CSP and clinical outcomes. References of included articles were hand searched.
PRINCIPAL FINDINGS
When platelets are stored at 1-6 °C, their metabolic rate is slowed, preserving hemostatic function for increased storage duration. Cold-stored platelets have superior adhesion characteristics under physiologic shear conditions, and similar or superior aggregation responses to physiologic agonists. Cold-stored platelets undergo structural, metabolic, and molecular changes which appear to "prime" them for hemostatic activity. While preliminary, clinical evidence supports the conduct of trials comparing CSP with RTP for patients with platelet-related bleeding, such as those undergoing cardiac surgery.
CONCLUSION
Cold-stored platelets may have several advantages over RTP, including increased hemostatic capacity, extended shelf-life, and reduced risk of bacterial contamination. Large clinical trials are needed to establish their potential role in the treatment of acutely bleeding patients.
Topics: Adult; Humans; Blood Preservation; Blood Platelets; Cold Temperature; Hemorrhage; Cardiac Surgical Procedures; Hemostatics
PubMed: 37831350
DOI: 10.1007/s12630-023-02561-9 -
Platelets Dec 2023F11 receptor (F11R)/Junctional Adhesion Molecule -A (JAM-A) is a transmembrane protein which belongs to the immunoglobulin superfamily of cell adhesion molecules.... (Review)
Review
F11 receptor (F11R)/Junctional Adhesion Molecule -A (JAM-A) is a transmembrane protein which belongs to the immunoglobulin superfamily of cell adhesion molecules. F11R/JAM-A is present in epithelial cells, endothelial cells, leukocytes, and blood platelets. In epithelial and endothelial cells, it takes part in the formation of tight junctions. In these structures, molecules of F11R/JAM-A located on adjacent cells form homodimers and thus take part in stabilization of cellular layer integrity. In leukocytes, F11R/JAM-A was shown to play role in their transmigration through the vascular wall. Paradoxically, the function of F11R/JAM-A in blood platelets, where it was primarily discovered, is much less understood. It has been proven to regulate downstream signaling of αIIbβ3 integrin and to mediate platelet adhesion under static conditions. It was also shown to contribute to transient interactions of platelets with inflamed vascular wall. The review is aimed at summarizing the current state of knowledge of the platelet pool of F11R/JAM-A. The article also presents perspectives of the future research to better understand the role of this protein in hemostasis, thrombosis, and other processes where blood platelets are involved.
Topics: Humans; Blood Platelets; Junctional Adhesion Molecule A; Endothelial Cells; Tight Junctions; Cell Adhesion Molecules; Receptors, Cell Surface
PubMed: 37246517
DOI: 10.1080/09537104.2023.2214618 -
BioEssays : News and Reviews in... Dec 2023Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α-granules...
Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α-granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet-derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet-secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, and impeding this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo-angiogenesis and the growth of newly formed myofibers, and reduces post-injury muscle force production. Platelets also contribute to the recruitment of pro-regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease.
Topics: Blood Platelets; Muscle, Skeletal; Signal Transduction; Wound Healing; Cytokines
PubMed: 37712935
DOI: 10.1002/bies.202300134 -
Journal of Clinical Laboratory Analysis Jan 2024Platelet concentrate (PC) transfusions are crucial in prevention and treatment of bleeding in infection, surgery, leukemia, and thrombocytopenia patients. Although the... (Review)
Review
BACKGROUND
Platelet concentrate (PC) transfusions are crucial in prevention and treatment of bleeding in infection, surgery, leukemia, and thrombocytopenia patients. Although the technology for platelet preparation and storage has evolved over the decades, there are still challenges in the demand for platelets in blood banks because the platelet shelf life is limited to 5 days due to bacterial contamination and platelet storage lesions (PSLs) at 20-24°C under constant horizontal agitation. In addition, the relations between some adverse effects of platelet transfusions and PSLs have also been considered. Therefore, understanding the mechanisms of PSLs is conducive to obtaining high quality platelets and facilitating safe and effective platelet transfusions.
OBJECTIVE
This review summarizes developments in mechanistic research of PSLs and their relationship with clinical practice, providing insights for future research.
METHODS
Authors conducted a search on PubMed and Web of Science using the professional terms "PSL" and "platelet transfusion." The obtained literature was then roughly categorized based on their research content. Similar studies were grouped into the same sections, and further searches were conducted based on the keywords of each section.
RESULTS
Different studies have explored PSLs from various perspectives, including changes in platelet morphology, surface molecules, biological response modifiers (BMRs), metabolism, and proteins and RNA, in an attempt to monitor PSLs and identify intervention targets that could alleviate PSLs. Moreover, novel platelet storage conditions, including platelet additive solutions (PAS) and reconsidered cold storage methods, are explored. There are two approaches to obtaining high-quality platelets. One approach simulates the in vivo environment to maintain platelet activity, while the other keeps platelets at a low activity level in vitro under low temperatures.
CONCLUSION
Understanding PSLs helps us identify good intervention targets and assess the therapeutic effects of different PSLs stages for different patients.
Topics: Humans; Blood Platelets; Platelet Transfusion; Thrombocytopenia; Hemorrhage; Blood Banks; Blood Preservation
PubMed: 38069592
DOI: 10.1002/jcla.24994